rs113042313

Variant names:

• chr17-37710601-C-T
• rs113042313
• NM_000458.4:c.1108G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000458.4(HNF1B):​c.1108G>A​(p.Gly370Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,614,076 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (2 hom.)
• Consequence: HNF1B NM_000458.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 4.53
• Publications: 4 publications found

Genes affected

HNF1B (HGNC:11630): (HNF1 homeobox B) This gene encodes a member of the homeodomain-containing superfamily of transcription factors. The protein binds to DNA as either a homodimer, or a heterodimer with the related protein hepatocyte nuclear factor 1-alpha. The gene has been shown to function in nephron development, and regulates development of the embryonic pancreas. Mutations in this gene result in renal cysts and diabetes syndrome and noninsulin-dependent diabetes mellitus, and expression of this gene is altered in some types of cancer. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

HNF1B Gene-Disease associations (from GenCC):

• renal cysts and diabetes syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• transient neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• medullary sponge kidney

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal dysplasia, bilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal dysplasia, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal hypomagnesemia 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• unilateral multicystic dysplastic kidney

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302846 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 72 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: 2.0703 (below the threshold of 3.09). GenCC associations: The gene is linked to unilateral multicystic dysplastic kidney, renal dysplasia, unilateral, renal cysts and diabetes syndrome, medullary sponge kidney, renal hypomagnesemia 2, renal dysplasia, bilateral, diabetes mellitus, noninsulin-dependent, transient neonatal diabetes mellitus, permanent neonatal diabetes mellitus.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06089571).
• BP6: Variant 17-37710601-C-T is Benign according to our data. Variant chr17-37710601-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379811.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000447 (68/152270) while in subpopulation AFR AF = 0.00159 (66/41554). AF 95% confidence interval is 0.00128. There are 1 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 68 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000458.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1B	NM_000458.4	MANE Select	c.1108G>A	p.Gly370Ser	missense	Exon 5 of 9	NP_000449.1
	HNF1B	NM_001411100.1		c.1108G>A	p.Gly370Ser	missense	Exon 5 of 8	NP_001398029.1
	HNF1B	NM_001165923.4		c.1030G>A	p.Gly344Ser	missense	Exon 5 of 9	NP_001159395.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1B	ENST00000617811.5	TSL:1 MANE Select	c.1108G>A	p.Gly370Ser	missense	Exon 5 of 9	ENSP00000480291.1
	HNF1B	ENST00000621123.4	TSL:1	c.1030G>A	p.Gly344Ser	missense	Exon 5 of 9	ENSP00000482711.1
	HNF1B	ENST00000613727.4	TSL:1	c.1030G>A	p.Gly344Ser	missense	Exon 5 of 7	ENSP00000477524.1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152152 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251104 AF XY: 0.0000958

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000111 AC: 162 AN: 1461806 Hom.: 2 Cov.: 33 AF XY: 0.0000880 AC XY: 64 AN XY: 727214

African (AFR) AF: 0.00299 AC: 100 AN: 33474

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.000894 AC: 54 AN: 60380

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152270 Hom.: 1 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74450

African (AFR) AF: 0.00159 AC: 66 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000563

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	-	HNF1B-related disorder (1)
-	1	-	Maturity onset diabetes mellitus in young (1)
-	-	1	not specified (1)
-	1	-	Renal cysts and diabetes syndrome (1)
-	1	-	Type 2 diabetes mellitus;C0431693:Renal cysts and diabetes syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.089
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.061	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L
PhyloP100		4.5
PrimateAI	Uncertain	0.49	T
Sift4G	Benign	1.0	T
Polyphen		0.23	B
Vest4		0.50
MVP		0.76
ClinPred		0.029	T
GERP RS		5.7
Varity_R		0.54
gMVP		0.50
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113042313; hg19: chr17-36070609;